Blood clotting prevents excessive blood loss from tissue damage. Under normal physiological conditions, a balance is maintained between blood flow and blood clot, dysfunction of which may yield either hemorrhage or thrombosis. The coagulation cascade controls the blood status and comprises two main pathways: the intrinsic pathway (triggered by damage to blood vessel walls and the subsequent interactions with nonphysiological surfaces such as collagen, lipoproteins, or bacteria) and the extrinsic pathway (initiated by endothelial damage or hypoxia). The two pathways converge at factor Xa, which cleaves prothrombin to thrombin, which further cleaves fibrinogen to form fibrin monomers. Factor XIIIa polymerizes fibrin monomers leading to the formation of the three-dimensional network of fibrin chains in the clot. Thromboembolic diseases (e.g. deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction) are all triggered by formation of a pathological clot and are the most frequent causes of death worldwide.
Anticoagulants are prescribed to treat and prevent thromboembolic diseases, e.g. by inhibition of one or more coagulation proteins. Among all proteins in the coagulation cascade, the common pathway enzymes, thrombin and factor Xa, have been successfully targeted with inhibitors. However, a number of drawbacks related to use of the inhibitors are known. For example, the thrombocytopenia and the patient-to-patient response variation of indirect factor Xa and thrombin saccharide-based inhibitors (heparins), the narrow therapeutic window and the genetic polymorphism of warfarin, and the life-threatening high risk of bleeding of particularly indirect and direct thrombin inhibitors (heparins, bivaluridin, argatroban, dabigatran) are major concerns. The safety profile of newer oral peptidomimetic anticoagulants including dabigatran and rivaroxaban is yet to be fully established, especially in cancer patients and pregnant women. Lastly, intracranial hemorrhage is fast becoming a severe complication of oral anticoagulant therapy with a mortality rate of 67% as in the case of warfarin.
There is a need in the art to develop new efficacious yet safe anticoagulants.